The widespread use of synthetic materials as implantable devices in the medical industry has been well documented. These implantable synthetic materials can generally be divided into two major groups, temporary/bioresorbable and long-term implants/non-bioresorbable. Examples of bioresorbable synthetic materials include polymers comprising poly 1-lactic acid (PLLA) and poly 1-glycolic acid (PLGA), which have long been used as surgical sutures. These materials have been fabricated into films, meshes and more complex three-dimensional structures depending on intended applications as described in U.S. Pat. No. 6,031,148.
An example of long-term implantable and non-bioresorbable materials is poly(tetrafluoroethylene) PTFE, which has been used in a wide array of medical implantable articles including vascular grafts (U.S. Pat. No. 5,718,973), tissue repair sheets and patches (U.S. Pat. No. 5,433,996). Polymeric hydrogels have also been adapted for surgical implants (U.S. Pat. No. 4,836,884); finding uses such as soft tissue and blood vessel substitutes.
Each of these materials possesses certain physical characteristics that make them suitable as implant materials. Such properties include good biocompatibility, strength, chemical stability, etc. which can be particularly important for a specific application. For example, PTFE has the strength and interconnecting fibril structure that is critical in fabrication of tubular grafts. Synthetic hydrogels, which have a superficial resemblance to living tissue due to high water content, display minimal irritation to surrounding tissues making them ideal as prosthetic devices. However, these synthetic materials also have limitations and disadvantages including a limited range of physical and biochemical properties. Thus, there remains a need to explore alternative materials more suitable for specific surgical applications.
The use of viscose or regenerated cellulose as implantable articles is known. Several investigators have studied tissue biocompatibility of cellulose and its derivatives (Miyamoto, T. et al., Tissue Biocompatibility of Cellulose and its derivatives. J. Biomed. Mat. Res., V. 23, 125-133 (1989)) as well as examined some specific applications for the material. The oxidized form of regenerated cellulose has long been used as a hemostatic agent and adhesion barrier (Dimitrijevich, S. D., et al. In vivo Degradation of Oxidized regenerated Cellulose. Carbohydrate Research, V. 198, 331-341 (1990), Dimitrijevich, S. D., et al. Biodegradation of Oxidized regenerated Cellulose Carbohydrate Research, V. 195, 247-256 (1990)) and are known to degrade much faster than the non-oxidized counterpart. A cellulose sponge studied by Martson, et al., showed biocompatibility with bone and connective tissue formation when implanted subcutaneously (Martson, M., et al., Is Cellulose sponge degradable or stable as an implantation material? An in vivo subcutaneous study in rat. Biomaterials, V. 20, 1989-1995 (1999), Martson, M., et al., Connective Tissue formation in Subcutaneous Cellulose sponge implants in rats. Eur. Surg. Res., V. 30, 419-425 (1998), Martson, M., et al., Biocompatibility of Cellulose Sponge with Bone. Eur. Surg. Res., V. 30, 426-432 (1998)): The authors summarized that the cellulose material can be a viable long-term stable implant. Other forms and derivatives of cellulose have also been investigated (Pajulo, O. et al. Viscose cellulose Sponge as an Implantable matrix: Changes in the structure increase production of granulation tissue. J. Biomed. Mat. Res., V. 32, 439-446 (1996).
However, the prior art fails to mention the possible use of a unique form of cellulose produced by certain unicellular organisms. In this regard, microbial cellulose produced by certain microorganisms has been known and studied for characteristics not found in plant cellulose, including high water content similar to hydrogels and exceptional strength like PTFE. Microbial cellulose can be synthesized in various shapes or sizes, and has excellent shape retention. These properties are mostly attributed to its unique laminar microfibrillar three-dimensional structure. The microfibrils arranged in a nonwoven manner are about 200 times finer than plant cellulose such as cotton fibers, yielding tremendous surface area per unit volume.
Even with the multitude of novel properties, microbial cellulose has not been fully utilized, and thus, limited applications have been suggested. For example, the use of microbial derived cellulose in the medical industry has been limited to liquid loaded pads (U.S. Pat. No. 4,788,146), wound dressings (U.S. Pat. No. 5,846,213) and other topical applications (U.S. Pat. No. 4,912,049). Mello et al., (Mello, L. R., et al., Duraplasty with Biosynthetic Cellulose: An Experimental Study. Journal of Neurosurgery, V. 86, 143-150 (1997)) published the use of biosynthetic cellulose similar to the one described in (U.S. Pat. No. 4,912,049) as a duraplasty material in an experimental animal study. Their results showed that the dried form of the microbial derived cellulose was adequate as a dural substitute. However, the material described by Mello et al. does not undergo a depyrogenation step and the material is fully dried while being stretched as described in U.S. Pat. No. 4,912,049 (BIOFILL™ Wound Dressing) that was originally developed for topical applications. In contrast, the instant invention provides a non-pyrogenic implantable material and uses a thermal dehydration method to partially dehydrate the surgical mesh. This endows the invention with superior conformability and absorption properties not available in previously described cellulosic materials.
In another aspect of the invention, various methods have been described in drying microbial cellulose. Blaney et al. in U.S. Pat. Nos. 5,580,348 and 5,772,646 describe an absorbent material which comprises a microbial polysaccharide having a mean pore size of about 0.1 to about 10 microns. The absorbent material is prepared by a process that comprises supercritical carbon dioxide drying of a microbial polysaccharide to remove the majority of the aqueous medium that is present when the microbial polysaccharide is produced.
The product and process of Blaney et al. differ from the present product and process discovered by the present inventors. The present inventors have determined a method of preparing implantable microbial cellulose by partially dehydrating the microbial-derived cellulose using a temperature induced removal of liquid that can be implanted without drying or that can use solvents like supercritical carbon dioxide to achieve a dry implantable material. Both materials would undergo sterilization either in the wet or dry form depending on the desired product. The product of Blaney et al. also differs from the present product in that the present product is capable of in vivo implantation as a result of non-pyrogenicity (non-endotoxicity), enhanced tensile strength and suture retention, sterilization by gamma irradiation, and biocompatibility.
A product that is similar to the material described in the present invention is the material in U.S. Pat. No. 6,599,518 Solvent Dehydrated Microbially-Derived Cellulose for Implantation. That invention describes a solvent dehydration using methanol, acetone, or other organic solvent to a water content of under 15%. The present invention differs from that material in that there is considerable more liquid remaining in the pad following dehydration so that it does not have to be rehydrated to improve its conformability as is necessary for the solvent dehydrated material. The present invention in its supercritical CO2-dried form also differs from the solvent dehydrated by being more absorptive.
While solvent dehydration results in a fully dried implantable material, prior to the present invention there has not been an acceptable partially dehydrated implantable material comprising microbial-derived cellulose. Accordingly, there remains a need for a partially dehydrated implantable material comprising microbial derived cellulose that can be used for a wide variety of medical and surgical applications. Methods of implanting microbial-derived cellulose for a variety of applications are also particularly desirable.